反应详情

A 0° C. solution of 4-(3-phenylpropyl)-imidazole-2-carboxylic (13d) (150 mg, 0.65 mmol) and N-(2-phenethyl)glycine tert-butyl ester (140 mg, 0.59 mmol) in 5 ml of anhydrous dimethylformamide was treated with diisopropylethylamine (154 μl, 0.89 mmol), hydroxybenzotriazole (160 mg, 1.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (136 mg, 0.71 mmol). After stirring for 36 h, the reaction was poured onto saturated aqueous sodium chloride and extracted with ethyl acetate (3×50 ml) The combined organic extracts were washed twice with saturated aqueous sodium bicarbonate (2×) and saturated aqueous sodium chloride (1×), dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil. Chromatography (flash, SiO2, 30% ethyl acetate/hexane) to give 160 mg (61%) of 23 as a white solid: 1H NMR (CDCl3) δ 7.38-7.14 (10H, m), 6.85-6.8 (1H, m), 4.84-4.76 (1H, d), 4.5-4.42 (1H, m), 4.07-4.0 (1H, d), 3.78-3.72 (1H, m), 3.12-2.94 (2H, 2×m), 2.75-2.55 (4H, m), 2.1-1.95 (2H, m), 1.5-1.45 (9H, 3×s). (3S)-{2-Phenethyl-[5-(3-phenylpropyl)-1H-imidazole-2-carbonyl]amino}acetyl amino) 4-oxobutanoic acid tert-butyl ester semicarbazone (24). The ester 23 (160 mg, 0.357 mmol) was treated with 25% trifluoroacetic acid/dichloromethane (7 ml) for 4 h. The reaction was concentrated in vacuo to afford 180 mg of the acid. The acid (180 mg, 0.357 mmol) was coupled to (3S)-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone (161 mg, 0.357 mmol) as describe for the preparation of 5a and 5b to give 86 mg (33%) of 24 (one diastereomer) as a white solid: 1H NMR (CDCl3) δ 10.9-10.3 (1H, 2 d), 10.08-9.78 (1H, 2 d), 9.25-9.15 (1H, m), 8.35-8.10 (1H, 2 m), 7.9-7.85 (1H, 2 s), 7.40-7.05 (10H, m), 6.9-6.75 (1H, m), 6.3-5.8 (1H, br s), 5.2-4.65 (2H, m), 4.35-3.5 (3H, m), 3.25-3.0 (2H, m), 2.9-2.45 (6H, m), 2.05-1.8 (2H, m), 1.4 (9H, s). (3S)-(2-{Phenethyl-[5-(3-phenylpropyl)-1H-imidazole-2-carbonyl]amino}acetylamino)-4-oxobutanoic acid trifluoroacetic acid salt (25) was prepared by the method described for 7a to afford 32 mg (82%) as a white solid: 1H NMR (CD3OD) δ 7.05-7.35 (m, 11H), 4.65 (m, 1H), 4.4 (m, 1H), 4.3 (s, 2H), 3.6-4.0 (m, 2H), 2.5-2.95 (m, 8H), 2.05 (m, 2H). 7-[S-(3-Phenylpropyl)-1H-imidazole-2-carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester (26). 4-(3-Phenylpropyl)imidazole-2-carboxylic acid (13d) was coupled to 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester hydrobromide (Smith et. al., J. Med. Chem., 31, pp. 875-85 (1988)) by the method described for 23 to afford 140 mg (65%) as a yellow gum: 1H NMR (CDCl3) δ 7.34-7.15 (5H, m), 6.98-6.8 (1H, 3 s), 5.7-5.65 (0.5 H, m), 5.2-5.1 (1H, m), 4.82-4.75 (0.5H, m), 4.4-4.35 (1H, m), 4.05 (1H, d), 3.75-3.7 (3H, 2 s), 3.4-3.3 (4H, m), 2.95-2.45 (8H, m), 2.05-1.95 (2H, m). (3S)-({7-[5-(3-Phenylpropyl)-1H-imidazole-2-carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carbonyl}-amino)-4-oxobutanoic acid tert-butyl ester semicarbazone (27). Following the procedure described for 4, the ester 26 was converted to its acid which was subsequently coupled to (3S)-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone as described for 24 to give 70 mg (33%) as a brown solid: 1H NMR (CD3OD) δ 7.28-7.10 (5H, m), 6.90 (1H, br s), 4.94 (1H, m), 3.96-3.86 (2H, q), 3.35-3.25 (4H, d), 3.0 (2H, s), 2.73-2.59 (6H, m), 2.0-1.92 (2H, m),1.44 (9H, s). (3S)-({7-[5-(3-Phenylpropyl)-1H-imidazole-2-carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carbonyl}-amino)-4-oxobutanoic acid (28) was prepared by the method described for 7a to afford 17 mg (26%) as a light brown solid: 1H NMR (CD3OD) δ 7.4 (s, 1H), 7.1-7.25 (m, 5H), 4.9 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.95 (s, 2H), 3.25-3.4 (m, 4H), 3.0 (d, 2H), 2.6-2.8 (m, 5H), 2.45 (m, 1H), 2.05 (m, 2H).

1. extractionextracted with ethyl acetate (3×50 ml) The combined organic extracts
2. washwere washed twice with saturated aqueous sodium bicarbonate (2×) and saturated aqueous sodium chloride (1×)
3. dry with materialdried (Na2SO4)
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customto give a brown oil